A wide range of existing and near-term therapeutics has great potential, but many of these agents possess drawbacks that slow or prevent implementation for aiding human health. For example, many therapeutics, drugs, or drug candidates have issues with delivery due to non-optimal pharmacokinetics and/or detrimental side effects due to their non-human nature. Injectable biologic drugs are one class that often needs assistance and includes molecules such as polypeptides (e.g., peptides, proteins) and polynucleotides (e.g., DNA, RNA, nucleic acid-polypeptide hybrids).
In particular, polypeptides (e.g., peptides, proteins, glycoproteins, etc.) or polynucleotides (e.g., polymers comprised of deoxyribonucleic acid or ribonucleic acids or nucleic acid-polypeptide hybrids, etc.) with therapeutic activity, often termed biologics, are becoming an ever increasingly useful type of modern medicine. However, these therapeutic agents may have problems due to short plasma half-life and/or negative effects with the body's systems.
Fortunately, the physical, chemical, and/or biological nature of a promising drug candidate may sometimes be assisted by modifying the parental drug. A widely used agent, poly[ethylene glycol] (PEG) has been approved by the Food and Drug Administration (FDA) for use with therapeutic “cargo” including small molecule drugs, polypeptides, and liposomes, for example. Covalent modification with a poly(ethylene glycol) [PEG] vehicle, called PEGylation, was one of the early attempts to rectify these issues with success, resulting in multiple FDA-approved drugs. The hydrophilic chains of PEG polymers increase the solubility of the cargo in water, protect the cargo when in the human body, and prolong the therapeutic action of the cargo. For example, PEGylation can shield the drug cargo molecule's surface from antibodies, regulatory enzymes, and/or clearance receptors. In addition, PEGylation can also increase the hydrodynamic size of the cargo, thereby preventing rapid elimination through renal filtration, which is especially important for therapeutics less than approximately about 60 to about 70 kDa.
However, PEG has some liabilities as a conjugating vehicle, including but not limited to, a lack of a safe degradation pathway, accumulation in some tissues, emerging immunogenicity, and potential triggering of the complement system. Due to its artificial nature, its chemical synthesis, and its potential harmful effects when ingested in large quantities over long periods of time, the use of PEG has significant drawbacks, and alternatives have been sought.
Therefore, other polymers have been experimentally employed as substitutes for PEG. Some of the promising candidates have been carbohydrates due to their perceived improved safety including modified starch (e.g. hydroxyethyl starch [HES]) and poly(sialic acid) [PSA] (see Table 1 below)). In a similar vein, genetic fusion of stretches of hydrophilic amino acid residues to protein cargo has also been employed, but this approach is applicable to a more limited subset of drugs (i.e., only human proteins).
Therefore, alternative modifying and/or coupling agents that can be used with drug cargo, and in particular polypeptides and polynucleotides, and which overcome the defects and disadvantages of the prior art, are continually being sought.